Abstract PD09-04: Homologous Recombination Deficiency (HRD) score predicts pathologic response following neoadjuvant platinum-based therapy in triple-negative and BRCA1/2 mutation-associated breast cancer (BC)

Abstract

Abstract Background: BC that arises in BRCA1/2 mutation carriers is characterized by defective homologous recombination DNA repair. Given the clinical potential for DNA repair-targeted therapeutics, Myriad Genetics has developed a tumor DNA-based assay that can identify underlying defects in the homologous recombination pathway, regardless of etiology, including identification of BRCA1/2 mutation carriers with high sensitivity. This study was designed to assess ability of the HRD score to predict pathologic response to neoadjuvant platinum-based therapy in early-stage triple-negative and BRCA1/2 mutation-associated BC. Methods: The HRD score was assessed in a cohort of 55 fresh frozen tumors from pts with clinical stage I-IIIA triple-negative and BRCA1/2 mutation-associated BC enrolled onto a single-arm, phase II study of neoadjuvant gemcitabine, carboplatin and iniparib. Following neoadjuvant therapy (4 cycles=11; 6 cycles=44), pathologic response was assessed using the residual cancer burden (RCB) index by a central pathologist. Twenty-nine tumors were obtained from responders (RCB 0/1) and 26 tumors were from non-responders (RCB 2/3). The HRD score was derived by count of the number of LOH regions (>15 Mb and < whole chromosome) observed in the tumor genome. Association of response to treatment and HRD score was performed by the Mann-Whitney U test. Results: Germline BRCA1/2 mutation status was known in all pts and 13/55 tumors were from carriers of deleterious BRCA1 (n = 9), BRCA2 (n = 3) or BRCA1&2 (n = 1) mutations. Two mutation carriers had ER+/PR+(>5%) BC. The mean HRD score for responders is 16.5 and no differences were noted between germline BRCA1/2 mutants vs. non-mutants. The mean HRD score for non-responders is 11.4. Among carriers of BRCA1/2 mutations, 12/13 achieved a favorable response. The one BRCA1 mutation carrier non-responder with TNBC had a low HRD score of 8. This pt was previously treated with chemotherapy twice 12 years prior for primary and locally recurrent contralateral TNBC. The p-value for association between response to treatment and HRD score by the Mann-Whitney U test is 0.004. If BRCA1/2 deficient samples are excluded, the association between response to treatment and HRD score remains significant (p = 0.02). Multivariate analysis that includes HRD score, BRCA1/2 genotype, age, stage, tumor grade, PAM50 subtype, ER/PR status, and cycles of therapy will be presented together with data from an additional 35 pts. Enrollment to the therapeutic trial is complete and final clinical results will be separately presented. Conclusion: The HRD score is significantly correlated with pathologic response to platinum-based chemotherapy in early-stage triple-negative and BRCA1/2 mutation-associated BC. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr PD09-04.